Differential diagnosis

1. Viral febrile illness
   • Influenza, COVID-19, other respiratory viruses
   • Dengue or chikungunya in endemic regions
   • Often fever, severe body ache, headache, anorexia, nausea, sometimes rash.
2. Malaria
   • Must be excluded promptly if in or returning from an endemic area.
   • Fever with chills, headache, malaise, nausea/vomiting are common. Fever periodicity may be absent early in disease. The CDC notes that malaria can progress rapidly and should be assessed promptly in exposed travellers. CDC travel guidance
3. Enteric fever (typhoid/paratyphoid)
   • Consider with unsafe food/water, contaminated water exposure, constipation or diarrhea, abdominal discomfort, coated tongue, hepatosplenomegaly, relative bradycardia.
4. Dengue
   • Consider especially with high fever, marked myalgia/arthralgia, retro-orbital headache, rash, leukopenia or thrombocytopenia.
   • Ask specifically about abdominal pain, persistent vomiting, mucosal bleeding, lethargy, or reduced urine output, which can indicate severe disease. CDC dengue warning signs
5. Leptospirosis
   • Exposure to floodwater, sewage, rodents, animals, farming.
   • Fever, severe calf/lumbar muscle pain, headache, conjunctival suffusion, jaundice or AKI can occur.
6. Rickettsial illness / scrub typhus
   • Rural or scrub exposure, ticks/mites, possible eschar, rash, lymphadenopathy, transaminitis.
   • Can present only with fever, headache, and myalgia initially.
7. Acute bacterial focus
   • UTI/pyelonephritis, pneumonia, acute gastroenteritis, hepatobiliary infection, sinusitis, dental infection, skin/soft-tissue infection.
   • Look for dysuria/flank pain, cough/dyspnea, diarrhea, focal abdominal pain, or local infection.
8. Meningitis/encephalitis
   • Must not miss if severe or worsening headache, neck stiffness, photophobia, altered sensorium, seizure, focal neurological deficit, or purpuric rash. Fever, chills, worsening headache and neck stiffness are concerning meningeal features. Goldman-Cecil Medicine, Meningitis section.

Suggested initial assessment and investigations

• Full vitals, hydration and mental-status assessment
• Focused exam: rash/eschar, conjunctiva, neck stiffness, chest, abdomen/hepatosplenomegaly, urine and neurological signs
• CBC with differential and platelet count
• Peripheral smear or rapid antigen test for malaria, with repeat testing if suspicion remains
• LFT, renal function, electrolytes, blood glucose
• Urinalysis and urine culture if urinary symptoms or no apparent source
• Blood cultures before antibiotics if patient appears toxic or enteric fever/sepsis is suspected
• Dengue NS1 antigen/PCR or serology based on day of illness and local protocol
• COVID-19/influenza testing if epidemiologically appropriate
• Chest X-ray if respiratory symptoms/signs
• Tests for typhoid, leptospirosis, scrub typhus or other local infections should be targeted to exposure and regional epidemiology. Do not rely on Widal alone to establish typhoid.

Urgent referral / emergency red flags

• Confusion, drowsiness, seizure, severe headache with neck stiffness or photophobia
• Hypotension, fainting, cold extremities, persistent rigors, breathing difficulty
• Repeated vomiting or inability to retain fluids
• Severe abdominal pain, bleeding, rash with petechiae/purpura
• Jaundice, markedly reduced urine output
• Pregnancy, immunosuppression, major comorbidity, or age extremes

• Best tests: Dengue NS1 antigen or RT-PCR plus dengue IgM.
• IgM usually becomes detectable after about day 3 to 5 and supports recent dengue, but may cross-react with other flaviviruses such as Zika, Japanese encephalitis, West Nile, or yellow fever.
• IgG alone is not diagnostic of acute dengue. It commonly reflects a prior dengue infection, past flavivirus exposure, or vaccination, and may remain positive lifelong. Goldman-Cecil Medicine, Diagnosis section.
• A positive NS1 or RT-PCR confirms acute dengue more specifically during the first 7 days of illness. CDC diagnostic guidance

• It detects antibodies to Salmonella O and H antigens, not the organism itself.
• False positives are common in endemic regions due to prior infection, vaccination, background antibodies, or cross-reaction.
• Titers often rise only in the second to third week of illness, so on fever day 5 it has limited value.
• A single positive Widal should not be the reason to label fever as typhoid or start antibiotics.
• A fourfold rise in paired titers taken about 1 to 2 weeks apart is stronger evidence, but this is usually not practical for acute decisions.

• CBC with platelet count and hematocrit
• Malaria smear/rapid antigen test
• Dengue NS1 plus IgM
• Blood culture if enteric fever is clinically suspected
• LFT, renal function, urine examination/culture as indicated

• Persistent fever with abdominal discomfort, constipation or diarrhea
• Exposure to unsafe food/water
• Coated tongue, hepatosplenomegaly, relative bradycardia
• No clearer alternative diagnosis

• It can be falsely positive from past infection, vaccination, or background antibodies in endemic regions.
• It can be falsely negative early in illness.
• A single titre does not reliably confirm acute typhoid.
• Blood culture, ideally collected before antibiotics, is preferred for confirmation. Culture sensitivity may fall after antibiotics.

• For suspected dengue: NS1/RT-PCR plus IgM, CBC, hematocrit, platelets.
• For suspected enteric fever: blood culture first; Widal only as supportive evidence and interpreted using local baseline titres and clinical findings.